Diabetes and Immune Checkpoint Inhibitors—Response
Authors: Alessio Cortellini, Antonio D'Alessio, David J. Pinato
Journal: Clinical Cancer Research (2023)

We thank Drs Yandamuri and Patnaik for their interest in our study on the impact of concomitant type 2 diabetes mellitus on clinical outcomes from immune checkpoint Inhibitors (ICI) in patients with solid tumors (1).In their work (2), Yendamuri and colleagues found a positive impact on survival of metformin use in patients with early-stage lung cancer, that was restricted to the high body mass index (BMI) subgroup, with concomitant evidence suggesting immunomodulatory effect of metformin within the tumor microenvironment. We performed a dedicated analysis among overweight and obese (BMI ≥ 25) patients with non–small cell lung cancer (NSCLC) included in our cohort (N = 368 patients), specifically looking at the potential association between metformin exposure at baseline and clinical outcomes. As reported in Supplementary Table 1, no baseline characteristic was associated with metformin use.Baseline metformin exposure was not associated with overall survival [OS, 10.8 months; 95% confidence interval (CI): 5.1–18.8; 30 events, vs. 13.4 months; 95% CI: 10.1–15.9; 223 events, log-rank P value: 0.38], nor with progression-free survival (PFS, 5.4 months; 95% CI: 3.9–11.7; 32 events vs. 6.6 months; 95% CI: 5.3–8.3; 262 events, log-rank P value: 0.92).In addition, we performed a propensity score matching procedure with a 1:2 ratio and 0.1 caliper including all available baseline covariates, between the metformin cohort and the control cohort to mitigate any potentially residual variability in baseline features (Supplementary Figure F1). Results from the matched cohorts confirmed that metformin use was not associated with OS (log-rank P value: 0.91) nor with PFS (log-rank P value: 0.87; Fig. 1).Several differences between our studies need to be taken into account. Importantly, Yendamuri and colleagues analyzed the effect of metformin on survival among patients with early-stage NSCLC irrespective of systemic oncological treatments. Our study cohort consisted of stage IV patients treated with ICI across different treatment lines. In trying to delineate the immune-modulating effects of metformin and preexisting diabetes, the complex interplay between the host metabolic status and immune function are unlikely dependent upon BMI only (3) in patients with cancer, where a number of other factors such as genetic makeup (4), dietary, and epidemiologic (5) differences need to be considered in interpreting inconsistencies in the association between metformin use and clinical outcomes.See the original Letter to the Editor, p. 4016The procedures followed were in accordance with the precepts of Good Clinical Practice and the declaration of Helsinki. Written informed consent was obtained from alive patients at the moment of data collection, while it was waived by competent authorities due to anonymized nature of patient data and retrospective design of the study for deceased patients. The study was approved by the respective local ethical committees on human experimentation of each institution, after previous approval by the coordinating center (University of L'Aquila, Internal Review Board protocol number 32865, approved on July 24, 2018).A. Cortellini reports personal fees from MSD, AstraZeneca, BMS, Oncoc4, IQVIA, Roche, GSK, Ardelis Health, Access Infinity, EISAI, and Pierre-Fabre outside the submitted work. A. D'Alessio reports personal fees from Roche outside the submitted work. D.J. Pinato reports personal fees from ViiV Healthcare, Bayer Healthcare, AstraZeneca, Roche, IPSEN, BMS, MiNa Therapeutics, DaVolterra, Exact Sciences, Mursla, Avamune; grants from MSD, GSK, and BMS outside the submitted work. No other disclosures were reported.The authors would like to acknowledge the infrastructural support provided by Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre and the Imperial College Healthcare NHS Trust Tissue Bank.A. D'Alessio acknowledges the support received from the NIHR Imperial BRC, the European Association for the Study of the Liver (Andrew Burroughs Fellowship), and Cancer Research UK (RCCPDB-Nov21/100008).A. Cortellini acknowledges support by the NIHR Imperial BRC.Grant funding from the Wellcome Trust Strategic Fund (PS3416) and Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG Grant ID 25697; D.J. Pinato).